Nu-[beta-(3-amino-2, 4, 6-triiodophenyl) propionyl] amino acids, nu-acyl derivativesthereof, and process



N -(3-AMlNO-2,4,6-TRIIODOPHENYL) PROPIO- NYL] AMlNO ACIDS, N-ACYLDERIVATIVES THEREOF, AND PROCESS Aubrey A. Larsen, Schodack Center, N.Y., assignor to Sterling Drug Inc., New York, N. Y., a corporation ofDelaware No Drawing. Application January 25, 1954 Serial No. 406,069

8 Claims. (Cl. 260-518) This invention relates toN-[fi-(3-arnino-2,4,6-triiodophenyl)propionyl]amino acids andN-[fi-(S-acylamino- 2,4,6-triiodophenyl)propionyl]amino acids having theformula Y Y 'cH.dHooNH-Y con wherein R is selected from the groupconsisting of.

hydrogen and. lower-alkyl groups, R is selected from the groupconsisting of hydrogen and lower-alkanoyl groups, and Y is alower-alkylene .radical, the sum of the number of carbon atoms in R andY not exceeding five. The invention also relates to a process forpreparing these new compounds.

My new compounds are useful as X-ray contrast agents and areparticularly valuable in' the visualization of the gallbladder(cholecystography).

In the above general formula the group R represents hydrogen or alower-alkyl group having from one to about four carbon toms. Thus when Ris a lower-alkyl group it can be methyl, ethyl, propyl, isopropyl,butyl, isobutyl and the like.

In the above general formula the group R represents hydrogen or alower-alkanoyl group having from one to about four carbon atoms. ThuswhenR'. .is a loweralkan-oyl group it can be formyl, acetyl, propionyl,bu

R OHKBHC O OH NHR wherein R and R have the meanings given above, firstwith an alkyl halocarbonate and then with an amino acid, H N-Y-COOH, ora salt or alkyl ester thereof. The reaction proceeds as follows: thetertiary amine salt of the iodinated phenylpropionic acid, for example,

2,840,602 Patented June' 24, .1958

lic

the triethylamine salt, first reacts with the alkyl halocarbonate, forexample isobutyl chlorocarbonate, preferably in an inert organic solventsuch as acetone or dimethylformamide, to give a mixed anhydride of .theformula' j V The mixed anhydride need not be isolated. The reactionmixture is then treated with an amino acid or a salt or alkyl esterthereof whereupon the desired product is produced along with carbondioxide and an alkanol as by-products. The reactions all take place 'reada ily at room temperature or below. If an alkyl ester ofan amino. acidis used, the product formed initially is an ester of the compounds ofthe invention, and a mild hydrolysis is necessary to produce the freeacids.

The compounds of the invention where R is a loweralkanoyl group canalternatively be prepared by direct acylation of the compounds where Ris hydrogen. The acylation is carried out by heating the free amino compound with an alkanoic acid, R-0H, or a reactive derivative thereof suchas the acid halide, R'--X, .where X is chlorine or bromine, or the acidanhydride, R' OR. A preferred method comprises, heating the free aminewith a lower-aliphatic acid anhydridein the presence of a catalyticamount ofQa strong acid such as sulfuric acid or perchloric acid. In thecase where R is formyl (HCO) the preparation is conveniently carried outby heating the free amine with formic acid and acetic anhydride.

The intermediate ,8-(3-arnino-2,4,6-triiodophenyl)pro pionic acids areprepared as described by Lewis and Archer, J. 'Am. Chem. Soc. 71, 3753(1949). The'intermediate B (3 acylamino 2,4,6 triiodophenyl)- propionicacids are prepared by acylation of the a-alkyl paragraph.

My new compounds are administered orallyeither as the free acid or inthe form of non-toxic salts derived from" neutralization of the acidswith non-toxic inorganic or organic bases, and the'non-toxic salts arealso within the purview of the invention. Exemplary. of preferred typesof non-toxic salts are the sodium salt, the diethanolamine salt and themethylglucamine salt. I

The following examples will further illustrate the in vention: a

. EXAMPLEI N [a ethyl B (3 amino 4 2,4,6 triiodopheuyl)propionyllglycine on Ethyl (3 amino 2,4,6 triiodophenyl)pro- "pionicacid (44 g.) and 11 ml. of triethylamine were chloric acid. The organicacid which precipitated was collected by filtration, recrystallized fromdilute acetone, washed with water and dried at 70 C., giving 10.5"g. ofN [a ethyl ,8 (3 amino- 2,4,6 triiodophenyl)- propionyllglycine, M. P..197.5198 C. (com). a

The solution was filtered and the filtrate was made acid with dilutehydro-.

Analysis.-- Calcd. for c rr nu o z I, 60.6. Found: I, 61.2.

N [a ethyl (3 amino 2,4,6 triiodophenyl)- propionyllglycine, whenadministeredorally to cats, gave excellent diagnostic shadows ofthegallbladder with-out toxic .manifestations. The shadows of thegallbladder were moredistinct than those produced by an equivalentamount of iodoalphionic acid, i. e., a-phen'y1-B(.4-hydroxy-3,5-diidophenyl)propionic acid.

. EXAMPLE 2 (a) a-Ethyl {3-(2,4,6 triiodo 3 ncetamidcphenyl) propionicacid A solution of 24 g. ofa-ethyl-fl-(2,4,6-triiodo-3-aminophenyl)propionic acid, 50 mlnof aceticanhydride and drops of concentrated sulfuric acid was heated on a steambath for five hours. The reaction mixture was poured into ice and heatedon a steam-bath to hydrolyze excess acetic anhydride. The solid materialwas collected by filtration, dissolved in dilute sodium hydroxidesolution and, reprecipitated with dilute hydrochloric acid. The.solidwas ,collected by filtration andrecrystallized first from acetic acidand thenfrom an ethyl acetate-acetone mixture to give 8.2 g. ofa-ethyl-fi-(2,4,6-triiodo-3 acetamidophenyl)propionic acid, M. P. 223225C. (corr.). l i

Analysis-Calcd. for'C H I NO :I, 62.1; C, 25.47; H, 2.30.; Found: I,62.0; C,25.77; H, 2.64.

i (b) N- uz-ethy 1-19 (3-acetamido-2,4,6-triiodophenyl)propionylJ-glycine Isobutyl chlorocarbonate. (7 g.) was added to asolution of 30.7 g. ofa-ethyl-B-(3-acetamido-2,4,6-triiodophenyl)propionic acid and 8 ml. oftrimethylamine in 100ml. of dimethylforrnamide. with stirring at 0 C.

The filtrate was made-acid toCongo red with 6 N hydrochloric acid andthe solid (solid no. 2) which separated was collected by filtration.vSolid no. 1, presumably the methyl esterof desired product,wassuspended injdilute ethanol, warmed on a steam bath, and dilutesodium hydroxidewas added in small portions to keep the solution faintlyalkaline. Aftersevenhours the mixture was filtered, the filtrateacidified, and the solid material which separated was collected byfiltration, dried and combinedwith solid no. 2, giving 27 g. ofN=[a-ethyl-fl-(3- acetamido-2,4,G-triiodophenyl)propionyll glycine. Asample when recrystallized by dissolving in ethanol, diluting with waterand cooling had the M. P. 239-240 C. (corn).

Analysis.Calcd. forC I-I I -N O I, 56.80. Found:

Following the manipulative procedure given above in Example 1, fl-( 3 7amino 2,4,6 triiodophenyl)propionic acid, u-methyl-fl-(3-amino-2,4,6triiodophenyUpropidnic acid,a-propylrfi(3-amino-2,4,6-triiodopheny1)propionic onic' acid,a-butyl-d(3-arnino 2,4;6-triiod0pheny1)propionic acid, q-butyl-B-(3arrfino-2,4,6-triiodophenyl) -propionic acid, andaisobutyl-fl-(3-amino-2,4,6-triiodophenyl)- propionic acid can beconverted respectively to N-[fi- (3-arnino-2,4,6-triiodophenyl)propionyl] glycine, N[umethyl-fl-(Ii-arnino-2,4,6-triiodopheny1)propionyl] glycine, N-.[r-propyl-fl-(3-amino-2,4,6 triiodophenyl)propionyl] glycine,N-[a-isoproyl-fl 3-amino-2,4,6-triiodophenyl)- propionyllglycine,N-[a-butyl-B-( 3amino-2,4,6-triiodophenyl)propionyl]glycine, andN-[a-isohutyl-fl-(S-amino- 2,4,6-triiodophenyl9propionyl]glycine. J

V propionyl] glycine, N- [a-ethyl-fl-(3propionamido-2,4,6-

triiodophenyl propionyl] glycine, N- [a-ethyl-fi-3-butyramido-2,4,6-triiodophenyl) propionyl] glycine, N- [or-ethyl- 3-3-isobutyramido-2,4,6-triiodophenyl) propionyl] glycine andN-[a-ethyl-p-(3-valeramido-2,4,6-triiodophenyl)pro- I pionyl] glycine.

Following the manipulative procedure given above in Example 1, using ,8-(3-amino-2,4,fi-triiodophenyl)propionic acid and alanine [H NCH(CH)COOH] as reactants, there is produced N-[343-amino-2,4,6-triiodophenyl)propionyllalanine.

Following the manipulative procedure, given above in Example 1, using,6-(3-amino-2,4,6-triiodophenyl)propionic acid and Balanine [H NCl-I CHCOOH] as reactants, there is. producedN-[{3-(3-amino-2,4,6-triiodophenyl) pro pionyl] B-alanine.

Following the manipulative procedure given above in Example 1, using,8-(3-amino-2,4,6-triiodophenyl)propionic' acid and valine [(CH CHCH(NH)COOH] as reactants, there is producedN-[[3-(3-amino-2,4,6-triiodophenyl) propionyl] valine.

Following. the manipulative procedure given above in Example 1, using[3-(3amino-2,4,6-triiodophenyl)propionic acid and leucine [(CH CHCHCH(NH )COOH] as reactants, there is producedN-[B-(3-amino-2,4,6-triiodophenyl propionyl leucine.

I claim: a 1. A memberof the groupconsisting of compounds having theformula I Iii -CH1CEQ ONH-Y-COOH NIH wherein R is a lower-alkyl grouphaving from one to four' carbon atoms, and Y is a lower-alkyleneradical, the sum of thenumber of carbon atoms in R and Y' not exceeding3. A compound having the formula CHzCHC ONH-Y-C O OH wherein R is alower-alkyl group having'from one to four carbon atoms, R is aloWer-alkanoyl group having from one to four carbon atoms, and Y is alower-alkylene radical, the sum of the number of carbon atoms in R and Ynot exceeding five.

4. A compound having the formula l GHaCHC ON'HCHzCO OH wherein R is alower-alkyl group having from one to four carbon atoms.

5. A compound having the formula R CHzHC ONHCHIC O OH R OHzlHC ONE-Y-C OOH 6 wherein R is selected from the group consisting of hydro gen andlower-alkyl groups having from one to four carbon atoms, R is selectedfrom the group consisting of hydrogen and lower-alkanoyl groups havingfrom one to four carbon atoms, and Y is a lower-alkylene radical, thesum of the number of carbon atoms in Y and R not exceeding five, thesteps which comprise reacting an aliphatic tertiary-amine sale of acompound having the formula l OHaCHCOOH first with an alkylhalocarbonate and then with a member of the group consisting of an aminoacid,

H N-YCO0H and salts and alkyl esters thereof.

UNITED STATES PATENT OFFICE Certificate of Correction Patent Nb;2,840,602 June 24,1958 Aubrey A. Larsen It is hereby certified thaterror appears in the printed specification of the above numbered patentrequiring correction and that the said Letters Patent should readcorrected below.

Column 1, line 38, for toms read -at0ms; column 3, line 9, fordroxy-3,5- dndophenyl) propionic read droxy-3,5-diiodophenyl)propionic-;lines 65 and 66, ion on1c acid,a-butyl-B-(3-amin0-2,4c,6-triiodopheny1)propionic acid,oi-butyl-fi-(iammo-2,4,6-tr1iodopheny1)-propiread ac'1d,a-isopropyl-fl-(3-amino-2,4,6-triiodopheny1)pr0p1onic acid,et-butyl-p-(3-amino-2,4,6-triiodopl1enyl)propicolumn 6, line 8, for saleread sa1t.

Signed and sealed this 2nd day of September 1958.

[SEAL] Attegfil KARL H. AXLINE, ROBERT G. WATSON, Attestz'ng Oyficer.Commissioner of Patents.

1. A MEMBER OF THE GROUP CONSISTING OF COMPOUNDS HAVING THE FORMULA